PROJECT SUMMARY/ABSTRACT This proposal is a for a five-year research program for a future junior faculty member, Dr. James Wisler, for studying cardiovascular cellular signaling under the mentorship of Dr. Robert Lefkowitz. Dr. Wisler is currently in his fellowship training in Cardiovascular Medicine at Duke University Medical Center and plans to further his scientific training in the laboratory of Dr. Lefkowitz. Dr. Lefkowitz has been a leader in the fields of cellular signaling, and cardiovascular biology for nearly four decades and has a long track record of training successful physician-scientists. The research and career development program devised will include specialized instruction, attendance at local and national scientific meetings, and an advisory committee that will broaden the training experience and help best prepare Dr. Wisler to obtain independent investigator funding by the end of this award period. In preliminary studies, we have identified a novel mechanism of aortic aneurysm development in murine models of both sporadic thoracic and abdominal aortic aneurysms as well as in a murine model of Marfan Syndrome, an inherited disorder complicated by the development of aortic aneurysms. These results suggest this pathway may have a more global pathogenic role in aneurysmal disease. This signaling pathway is dependent on angiotensin type IA receptor signaling. In addition, this pathogenic signaling cascade is negatively regulated by another G protein-coupled receptor (GPCR), the MAS receptor. Although the MAS receptor was de-orphanized over a decade ago, controversy exists over the precise mechanisms of activation and signaling mediated via this receptor. The aims of this proposed research are to: 1) to define the transducer coupling and signaling profiles downstream of the MAS receptor; 2) to delineate the properties of Mas receptor activation using biophysical approaches; and 3) to determine if Mas receptor signaling effects aortic aneurysm formation. Our lab is in a unique position to answer these questions as we have unparalleled expertise in the investigation of in vitro and in vivo GPCR biology. We expect these studies to result in important insights into the molecular mechanisms of aortic aneurysm formation as well as how regulation of these mechanisms might be exploited therapeutically via targeting of a novel, counter-regulatory receptor.